Salt of polymannuronic acid and dihydroquinidine

ABSTRACT

Salt of polymanuronic acid and dihydroquinidine is prepared by reacting stoichiometric quantities of the polymanuronic acid and dihydroquinidine at 70*-75*C in the presence of a solvent until the pH of the reaction mixture is about 7.

United States Patent 1 Coho Barrachina June 3,1975

[ SALT OF POLYMANNURONIC ACID AND DIHYDROQUINIDINE [75] lnventor: Gonzalo Cobo Barrachina, Madrid,

Spain [73] Assignee: Laboratorios Berenguer Beneyto S.A., Madrid, Spain [22] Filed: May 7, 1973 [21] Appl. No.: 357,702

Related US. Application Data [62] Division of Ser. No. 144,044, May 17, 1971,

abandoned.

[30] Foreign Application Priority Data May 21, 1970 Germany 2024847 [52] US. Cl. 260/284; 260/345.7; 424/259 [51] Int. Cl C07d 43/24 [58] Field of Search 260/284 [56] References Cited UNITED STATES PATENTS 3,479,359 11/1969 l-lalpern 260/284 Primary Examiner--Donald G. Daus Attorney, Agent, or Firm-Wenderoth, Lind & Ponack [5 7] ABSTRACT Salt of polymanuronic acid and dihydroquinidine is prepared by reacting stoichiometric quantities of the polymanuronic acid and dihydroquinidine at 7075C in the presence of a solvent until the pH of the reaction mixture is about 7.

1 Claim, 7 Drawing Figures PATENTEUJUI-I3 I975 3,887,562 SHEET 1 FIG -1 Gonzalo COBO BARRACHINA, Inventor 'MJZIMizhW I Attorneys PAW-mum 1915 3,887,562

SHEET 2 Sol 3%oo zsbo who who \660 FIG 2 12500 1400 who who so'o e25 Gonzalo COBO BARRACHINA, Inventor Attorneys FIG-3 FIG-3a Gonzalo COBO BARRACHINA, Inventor 'MMMMJLL XLAW Attorneys PATENTEDJUH3 m5 7 3.887.562

SHEET 4 o 3000 2500 zobo 1860 \660 FIG -4 1600 who 1260 1000 so'o 62's FIG -4a Gonzalo COBO BARRACHINA, Inventor Attorneys SALT OF POLYMANNURONIC ACID AND DIHYDROQUINIDINE This is a division, of application Ser. No. 144,044, filed May 17, l97l, now abandoned.

The quinidine base is a well-known alkaloid, stereoisomer of quinine, in whose nucleus of quinuclidine a vinyl group is found which, by catalytic hydrogenation, gives rise to dihydroquinidine:

The cardic-dynamic and anti-arrhythmio properties of this alkaloid are known, but its oral administration in the form of conventional inorganic salts of the quinidine base presents the disadvantage of producing certain disturbances. it is generally recognised that the gastro-intestinal disturbances that appear after the use of conventional compounds of quinidine are due, in the majority of cases, to a local irritation more than to a systematic toxic manifestation. It is believed that this irritation is due to the ionic shock that is produced in the gastro-intestinal mucosa as a consequence of the liberation by rapid dissociation of the irritant ions of the conventional inorganic salts of the quinidine base.

The solutions proposed up to now to palliate these disadvantages have proved to be insufficient. Among the methods that have been suggested to prevent this undesirable effect are the diminution of the dose, which supposes a diminution of the therapeutic effect; the utilization of parenteral injection which is troublesome in the case of prolonged treatments: specialenteric coverings of the tablets, which protect the stomach but not the intestine, or the addition of substances which protect the gastric and intestinal mucosa, such as anti-noids or a neutraliser.

The purpose of this invention is to reduce the undesirable effects mentioned, without reducing the therapeutic effect or having recourse to troublesome forms of administration.

These and other advantages which will appear in the description that follows are achieved by means of the provision of a salt of dihydroquinidine with polymanuronic acid, which salt is not very soluble and has a very low and constant index of dissociation; said salt being easily obtained since same presents a very powdery structure, whereby a grinding phase is not necessary.

Dihydroquinidine has been shown to possess an antiarrhythmic activity superior to that of quinidine, for which reason the same results are obtained with substantially reduced doses, of the order of per cent less.

The polymanuronic acid, which is not dissolved or absorbed in the stomach. becomes slowly dissolved in the intestinal tract. It is endowed with emollient properties, and increases its volume several times in contact with humidity, for which reason it acts as a protector of the digestive mucosa, forming a film over the latter and preventing local irritation. Likewise, said polymanuronic acid is stable to molecular degradation up to a pH of 10, which makes it totally inabsorbible in the digestive tube. The mentioned acid does not contain sterifying methoxyl groups, whereby its carboxyl groups are free for the formation of salts. This acid also has the great advantage of extraordinarily increasing its volume of absorbing water. Concretely, it increases its volume about twice that of the polygalaoturonic acid in spite of the fact that both acids absorb water in the same proportion. Thus, it is indeed interesting, since, if the essential objects now sought for is the protection of the digestive mucosa for preventing the irritating action of the quindine ions, there is no doubt whatsover that this function is directly related to the volume acquired by said salts since the greater the volume, the greater the surface of mucosa covered.

Again, the fact of a slower dissociation of the salt of polymanuronic aoid and dihydroquinidine provide a more uniform intestinal absorption, with more stable and lasting hematic levels of dihydroquinidine. This gives it a kind of effect similar to that of depot administration,-which undoutedly facilitates its administration and makes it more comfortable in the case of patients who habitually have to take various doses repeated throughout the day and the night.

Polymanuronic aoid is formed by long polymer chains of manuronic aoid cycled in pyranosic form in such a manner that its carboxyl groups remain free.

it is a relatively strong polyacid, capable of decomposing carbonates, and which can form inorganic and organic salts as well as esters. The length of its chain depends on the processes employed in its extraction and purification from certain classes of algae which contain it, and on the resultant hydrolysis that it under- COOH goes, its molecular weight being, in general, of the' the latter it swells absorbing from 200 to 300 times its weight in water and forming a gel. This gel is not attacked by the gastric juice and dissolves slowly in the alkaline medium of the intestine.

in the reaction of polymannuronic acid with dihydroquinidine a yellowish odourless powder with a bitter taste is obtained, which decomposes at C, and which proves to be insoluble in common solvents, except aqueous methanol and ethanol and propylene glycol.

The empiric formula of dihydroquinidine polymanuronate is (C ,;H O,,N. the value of depending on the number of monomer units existing in the chain of the acid. The compound presents 58.18 per cent of carbon, 6.76 per cent of hydrogen and 5.22 per cent of nitrogen, and contains 60.46 per cent of dihydroquinidine.

The ultraviolet spectrum of the compound, FIG. 1, curve 1, is, at its maxima and minima, that of dihydroquinidine, H6. 1, curve 2, because of the latter being the only part of the molecule that absorbs in this region. Maxima of absorption are obtained at 280 nm and 333 nm and minima at 253 nm and 301 nm.

The infrared spectrum is characteristic and that of dihydroquinidine alone, FIG. 2, can be compared with that of its stoichiometric mixture with polymannuronic acid, FIG. 3, and with that of the compound, FIG. 4, the existence of the latter being demonstrated by the peak that is found at 1,615 cm corresponding to carboxylates and the disappearance of the peak corresponding to carboxyls and which appears as a broader band towards 1,710 cmas well as by its solubility.

Hydroquinidine is soluble in methanol, in ethanol of 96, chloroform, propylene glycol, acetone, etc. Poly-. mannuronic acid is insoluble in these solvents, is only very slightly soluble in water, and is soluble in solutions of alkalis and/or carbonates. The compound is insoluble in methanol, ethanol of 96, chloroform, cold propylene glycol, acetone, etc., being soluble in methanol and/or ethanol at 50 per cent and in hot propylene glycol. A simple mechanical mixture of polymannuronic acid and hydroquinidine will consequently partially dissolve (the hydroquinidine) in one of these solvents, while the compound will remain insoluble.

A mechanical mixture of polymannuronic acid and hydroquinidine melts between 1 12 and 1 17 C. At this same temperature the polymannuronic acid begins to darken. At 170 C the hydroquinidine melts. At 180 C the acid ceases to darken, and the compound, which becomes totally decomposed at 190 C commences to darken.

The rotatory power of (C H o N- is: +77.3 (Propylene glycol, c 0.5).

The preparation of dihydroquinidine polymanuronate should begin with an evaluation of the polymannuronic acid to establish its chemical equivalent and to know the proportion of dihydroquinidine with which it will react. The course of the reaction can be followed, in addition to observing the change of aspect of the reacting mixture, by the pH values which, on the termination of the reaction, will be practically neutral. The compound is separated by filtration and is purified by means of repeated extractive washings. Finally, the product presents the aspect of a fine dry powder, of slightly yellowish colour, stable in air at ambient temperature and up to some 150 C.

The reaction between the polymannuronic acid and the dihydroquinidine can be brought about when both compounds are found in a free state, or by means of a double decomposition between a metal salt of the polymannuronic acid and an appropriate organic and inorganic salt of the dihydroquinidine.

Once the polymannuronic acid has been valued and the stoichiometric equivalent of dihydroquinidine has been calculated, the product can be obtained in the following manner:

olymannuronic acid is suspended in a hydroalcoholic solvent, and to this suspension there is added, while stirring, an equal volume of the same solvent containing the necessary quantity of dihydroquinidine. The mixture is kept at a moderate temperature and is agitated until the reaction finalizes. It is then rapidly cooled and filtered. By evaporating the solvent in vacuum and at the lowest possible temperature, new quantities of the compound are recovered. The dry residue is washed with absolute ethanol, is filtered and is again dried.

Once the reaction has terminated. the product may also be isolated by concentrating it in vacuum until it forms a paste. Then a double volume of acetone is added, it is cooled, it is left in repose for 24 hours, it is filtered and the product is dried.

Another mannerof isolating the product consists of evaporating the solvent in a vacuum atomizer apparatus. The residue in powder form is washed with acetone or absolute ethanol, is filtered and is dried.

Alternatively, it is suspended in water and polymannuronic acid, and to this suspension, which is heated and stirred, there is added an equal volume of a solution of the dihydroquinidine necessary in an alcohol of low molecular weight. The separation of the product is effected by any of the three processes given above. I Again, the polymannuronic acid can be previously dissolved in the necessary quantity of sodium hydroxide 0.1 N or in another hydroxide, carbonate or bicarbonate of alkaline or alkaline-earth metal.

Instead of dihydroquinidine in its basic form, one of its salts may be employed with an acid such as sulphuric, hydrochloric, hydrobromic or nitric;

For any process that is followed for obtaining hydroquinidine polymanuronate, the beginning consists of an evaluation of the polymannuronic acid by suspending in water 0.500 grammes of the latter and titrating with sodium hydroxide 0.1 N, employing phenolphthalein as an indicator.

From this evaluation there is deduced the stoichiometric equivalent of dihydroquinidine for a given quantity of the acid. In the experiment carried out the equivalence was 10.0 grammes of polymannuronic acid for 15.8 grammes of dihydroquinidine, and with these quantities the obtention tests were carried out.

EXAMPLE 1 l0 grammes of polymannuronic acid are suspended in 400 ml of methanol at 50 per cent v/v and, by means ofa funnel fitted with a tap, it is slowly added (the time taken being from one to one and a half hours) to a suspension of 15.8 grammes of dihydroquinidine in another 400 ml of the same solvent contained in a 2-litre wash bottle with reflux refrigerant, and mechanical agitation keeping it in a water bath at C.

The process of reaction, in all cases, should last for a minimum of 2 hours, more than three hours not being necessary.

Once the reaction has been completed. the wash bottle is cooled in a bath of crushed ice mixed with sodium chloride to give a temperature of at least l0C (a refrigerated chamber may also be employed). At the end of some 6 hours it is rapidly filtered by means of a Buchner funnel and the product is dried at a temperature below 1 10C.

The filtered solvent can be employed in a new obtention process, or can be evaporated by means of a vacuum at a temperature not exceeding 60C., thus recovering a new portion of the product.

The dry residue is washed with absolute ethanol, is filtered and is again dried.

EXAMPLE 2 In a 2-litre wash bottle with mechanical agitation and reflux refrigerant, l0 grammes of polymannuronic acid and 400 ml of water are placed. The wash bottle is heated in a water bath up to 75C, and there is slowly added, by means of a funnel fitted with a tap.

15.8 grammes of dihydroquinidine in 400 ml of methanol or of ethanol of 96. As in the case of the previous example, the reaction will be completed in less than three hours.

The reaction mixture is distilled until it reaches the consistancy of a paste at a temperature between 50 and 60C and a pressure of 40 to 60 mm of mercury. To the residual paste there is added, under cold conditions, a volume of acetone that is approximately double. The mixture is left undisturbed overnight in a redine. and after drying it is again washed with absolute ethanol or with acetone.

In all, there are established three processes for obtention and three processes for separation of the product. it being possible to employ for its production any of the nine combinations possible.

frigerator which maintains it below 5C, it is filterf'ed and the product is dried.

EXAMPLE 3 The residue is washed with water until the elimination of the corresponding salt that is formed with the cation of the acid and the anion of the dihydroquinil. A dihydroquinidine salt of polymanuronic acid having the following properties:

a. a fine odorless powder of yellowish color and bitter taste,

b. stable in air at from ambient temperature to about 0. empirical formula (C H O NQ wherein x is the number of monomer units of manuronic acid,

d. dihydroquinidine content of 60.46%,

e. infrared spectrum indicating a peak at 1,615 cm,

with a broad band at 1,710 cm,

f. insoluble in methanol, 96% ethanol, chloroform, cold propylene glycol and acetone, and soluble in 50% methanol, 50% ethanol and hot propylene glycol,

g. total decomposition at C,

h. rotation of +77.3 (propylene glycol, c 0.5),

i. ultraviolet spectrum indicating a maxima absorption at 280 and 333 nm and a minima absorption at 253 and 301 nm, and

j. carbon content of 58.18%, hydrogen content of 6.76% and nitrogen content of 5.22%. 

1. A DIHYDROQUINIDINE SALT OF POLYMANURONIC ACID HAVING THE FOLLOWING PROPERTIES: A. A FINE ODORLESS POWDER OF YELLOWISH COLOR AND BITTER TASTE, B. STABLE IN AIR FORM AMBIENT TEMPERATURE TO ABOUT 150*C, C. EMPIRICAL FORMULA (C26H34O8N2)X, WHEREIN X IS THE NUMBER OF MONOMER UNITS OF MANURONIC ACID, D. DIHYDROQUINIDINE CONTENT OF 60.46%, E. INFRARED SPECTRUM INDICATING A PEAK AT 1,615 CM-1, WITH A BROAD BAND AT 1,710 CM-1, 